Tropomyosin receptor kinase (Trk) is a neurotrophin (NT) receptor tyrosine kinase which has an NT-binding domain extracellularly and a kinase domain intracellularly, and is classified into TrkA being a receptor for nerve growth factor (NGF), TrkB being a receptor for brain-derived neurotrophic factor (BDNF) and NT-4/5, or TrkC being a receptor for NT-3. These Trk receptors are reported to be highly expressed in nerve tissues and be involved in neuronal differentiation and maintenance, and signal transduction (Non Patent Literature 1).
The NGF is known to increase in concentration in painful diseases such as arthritis, pancreatitis, cystitis, chronic headache, diabetic neuropathy, and cancers. In addition, it has been reported that administration of the NGF to a human or a rat induces pain (Non Patent Literature 2). Moreover, it is known that human loss-of-function mutation in the NGF or TrkA results in congenital analgesia (Non Patent Literature 3) and that pain symptoms disappear in NGF or TrkA knockout mice (Non Patent Literatures 4 and 5). Therefore, it is considered that the NGF/TrkA pathway is strongly involved in the development of pain in vivo.
It has been shown in clinical studies and nonclinical studies that inhibitors of the NGF/TrkA pathway, namely anti-NGF antibodies, anti-TrkA antibodies, small molecule Trk inhibitors, and the like are able to ameliorate various pain symptoms. For example, it has been reported that they are effective for pain associated with osteoarthritis, chronic low back pain, rheumatoid arthritis, bone fracture, interstitial cystitis, and chronic pancreatitis, and for pain such as neuropathic pain, cancer pain, complex regional pain syndrome, and migraine (Non Patent Literatures 2 and 6 to 9).
It is known that Trk receptors including TrkA are involved in various cancers such as neuroblastoma, ovarian cancer, colon and rectal cancer, melanoma, head and neck cancer, gastric cancer, lung cancer, breast cancer, glioma, astrocytoma, medulloblastoma, cholangiocellular carcinoma, secretory breast carcinoma, salivary gland carcinoma, prostate cancer, pancreatic cancer, thyroid papillary carcinoma, and adult myeloid leukemia due to mutations and the like including overexpression, activation, and gene fusion. It has been shown in clinical studies and nonclinical studies that Trk inhibitors inhibit tumor proliferation (Non Patent Literatures 10 to 14).
Also, it is reported that: the TrkA receptor is also expressed in inflammatory cells such as mast cells and eosinophils, immunocompetent cells such as monocytes, macrophages, T cells, and B cells, central nerve cells including cholinergic nerves, and the like; and the NGF/TrkA pathway is also involved in diseases such as asthma, rhinitis, atopic dermatitis, ulcerative colitis, Crohn's disease, psoriasis, multiple sclerosis, systemic lupus erythematosus, and Alzheimer's disease (Non Patent Literatures 15 to 21).
For those reasons, the creation of a drug having a TrkA inhibitory activity can be expected to produce a novel type of therapeutic and/or preventive agent because the created drug has a possibility of application to the treatment of pain, cancers, inflammatory diseases, allergic diseases, and autoimmune diseases, and the like.
Derivatives having a urea structure and exhibiting a TrkA inhibitory action are disclosed in, for example, International Publication No. WO2015/175788 (Patent Literature 1), International Publication No. WO2015/039333 (Patent Literature 2), International Publication No. WO2014/078378 (Patent Literature 3), and International Publication No. WO2014/078325 (Patent Literature 4). However, the derivatives disclosed in these literatures do not include a compound with a tetrahydronaphthyl structure which is a characteristic structure of the present invention, and there is no disclosure or suggestion for a compound with a tetrahydronaphthyl structure.
Meanwhile, although International Publication No. WO2014/078454 (Patent Literature 5) discloses a derivative having a tetrahydronaphthyl structure and exhibiting a TrkA inhibitory action, the patent is a urea derivative having a pyrazole ring and does not disclose a specific compound of the present invention.
Here, in drug development, it is required to satisfy strict criteria in various aspects such as absorption, distribution, metabolism, and excretion as well as the intended pharma cological activities. There are requirements concerning various problems to be considered such as drug interaction, desensitivity or tolerance, gastrointestinal absorption by oral administration, rate of transfer into the small intestine, absorption rate and first pass effect, organ barrier, protein binding, induction or inhibition of drug metabolizing enzyme, excretion route and body clearance, and application method (application part, method, purpose). It is hard to find a drug which satisfies these requirements. However, these problems seem to be always associated with medicines.